Open questions on viral frameshifting: Exploiting the structural plasticity of the frameshifting element for therapeutic intervention.

Programmed ribosomal frameshifting (PRF) is a specialized controlled-slippage genetic mechanism that viruses such as SARS-CoV-2 and HIV-1 use to shift the reading frame during translation. This process is used in compact viral genomes to enhance their protein repertoire, maintain a precise balance of viral proteins necessary for successful replication, and enhance survival within a host. Because this mechanism is vital to the viral life cycle and remains consistent across strains, frameshifting has emerged as a promising therapeutic target for new antiviral therapeutic strategies. However, the complexity of the frameshifting process has posed many challenges that need to be addressed so that the relationship between cellular mechanisms and viral replication can be exploited for novel therapeutics. In this review, we introduce frameshifting mechanisms, define open questions being explored by many modeling and experimental studies, and illustrate how coarse-grained graphs have been used in our lab to study frameshifting mechanisms. Specifically, we describe how conformational landscapes, mutation designs of frameshifting elements, all-atom molecular dynamics, and enhanced sampling simulations have been combined with chemical mapping and functional experiments to advance studies of three viral systems employing -1 PRF: SARS-CoV-2, HIV-1, and chikungunya.